This invention relates to novel N-alkyl-N-iminomethyl derivatives (I) of the antibiotic thienamycin (structure II, below). Such compounds, including their O- and carboxyl derivatives and their pharmaceutically acceptable salts are useful as antibiotics. This invention also relates to processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds, and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated. The compounds of the present invention may generically be represented by the following structural formula (I): ##STR2## which is one canonical form of a single resonant structure: ##STR3## Structure I may more conveniently be represented by the symbol: ##STR4## wherein: "Th" symbolizes the bicyclic nucleus of thienamycin and the OH, amino, and carboxyl groups of thienamycin are illustrated;
X is oxygen, sulphur or NR'(R'=H or alkyl having 1-6 carbon atoms); and R.sup.4 is, inter alia, representatively selected from the group consisting of hydrogen, conventional blocking groups such as trialkylsilyl, acyl and radicals (R.sup.4) giving rise to the pharmaceutically acceptable salt, ester and amide moieties (--COXR.sup.4) known in the bicyclic 3-lactam antibiotic art (the definition of R.sup.4 is given in greater detail below); PA1 R.sup.3 is hydrogen; or PA1 R.sup.3 is (1) acyl (generically the group OR.sup.3 is classifiable as an ester); or (2) R.sup.3 is selected from alkyl, aryl, aralkyl and the like such that the group OR.sup.3 is generically classifiable as an ether; the term "acyl" is by definition inclusive of the alkanoyls including derivatives and analogues thereof such as thio analogues wherein the carbonyl oxygen is replaced by sulphur; as well as sulphur and phosphorous acyl analogues such as substituted sulfonyl-, sulfinyl-, and sulfenyl- radicals, and substituted P(III and V) radicals such as substituted phosphorous-, phosphoric-, phosphenous- and phosphonic- radicals, respectively; such acyl radicals of the present invention are further defined below, as are the radicals 2. (above) which constitute the ether embodiments of the present invention PA1 (R.sup.3 is defined in greater detail below; PA1 R.sup.5 is, inter alia, alkyl, alkenyl, aryl or aralkyl; for example, R.sup.5 may be selected from the group consisting of: substituted and unsubstituted: lower alkyl having 1-10 carbon atoms, alkenyl having 2-10 carbon atoms, alkynyl having 2-10 carbon atoms, ring substituted and unsubstituted: cycloalkyl, cycloalkenyl, cycloalkenylalkyl, and cyclo-, alkylalkyl having 3-6 ring carbon atoms and 1-6 carbon atoms in the alkyl chain; aryl having 6-10 carbon atoms; aralkyl having 6-10 ring carbon atoms, and 1-6 carbon atoms in the alkyl chain; mono- and bicyclic heteroaryl and heteroaralkyl comprising 4-10 ring atoms one or more of which is selected from oxygen, nitrogen and sulphur and 1-6 carbon atoms in the alkyl chain; and wherein the ring or chain substituent (or substituents) in the aforementioned radicals is selected from: halo such as chloro, bromo, iodo and fluoro, azido, cyano, amino, mono-, di- and trialkyl substituted amino wherein the alkyl has 1-6 carbon atoms, hydroxyl, alkoxyl having 1-6 carbon atoms, alkylthioalkyl having 1-6 carbon atoms, carboxyl, oxo, alkoxylcarbonyl having 1-6 carbon atoms in the alkoxyl moiety, acyloxy comprising 2-10 carbon atoms, carbamoyl, and mono- and dialkylcarbamoyl wherein the alkyl groups have 1-4 carbon atoms, cyanothio (-SCN), and nitro; R.sup.5 is further defined below: PA1 R.sup.6 is selected from the group consisting of hydrogen, R, OR SR and -NR.sup.1 R.sup.2 ; PA1 R.sup.1 and R.sup.2 are independently selected from R, hydrogen, nitro, hydroxyl, alkoxyl having 1-6 carbon atoms, amino, mono- di- and trialkylamino wherein the alkyl moieties each comprise 1-6 carbon atoms; R.sup.1 and R.sup.2 may be joined together to form a substituted or unsubstituted mono- or bicyclic heteroaryl or heterocyclyl comprising (together with the nitrogen atom to which they are attached) 4-10 atoms one or more of which may be an additional hetero atom selected from oxygen, sulphur or nitrogen; R, R.sup.1 and R.sup.2 are substituted or unsubstituted: cyano; carbamoyl; carboxyl; alkoxycarbonyl and alkyl having from 1 to about 10 carbon atoms; alkenyl having from 2 to about 10 carbon atoms; alkynyl having from 2 to about 10 carbon atoms; cycloalkyl having from 3 to 10 carbon atoms; cycloalkylalkyl and cycloalkylalkenyl having from 4 to 12 carbon atoms; cycloalkenyl, cycloalkenyl-alkenyl, and cycloalkenylalkyl having 3-10, 4-12 and 4-12 carbon atoms, respectively; aryl having from 6 to 10 carbon atoms, aralkyl, aralkenyl, and aralkynyl having from 7 to 16 carbon atoms; mono- and bicyclic heteroaryl and heteroaralkyl which typically comprise 4 to 10 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur, or nitrogen and wherein the alkyl moiety of the heteroaralkyl radical comprises 1 to about 6 carbon atoms; mono- and bicyclic neterocyclyl and neterocyclylalkyl which typically comprises 4 to 10 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur or nitrogen and wherein the alkyl moiety of the heterocyclylalkyl radical comprises from 1 to about 6 carbon atoms; and wherein the above-mentioned substituent or substituents on R, R.sup.1, R.sup.2 or on the ring formed by the joinder of R.sup.1 and R.sup.2, are selected from the group consisting of: halo, such as chloro, bromo, iodo and fluoro; azido; alkyl having 1-4 carbon atoms; thio; sulpho; phosphono; cyanothio (-SCN); nitro; cyano; amino; hydrazino; mono-, di- and trialkyl substituted amino, and hydrazino wherein the alkyl has 1-6 carbon atoms; hydroxyl; alkyl having 1-4 carbon atoms; alkoxyl having 1-6 carbon atoms; alkylthio having 1-6 carbon atoms; carboxyl; oxo; alkoxylcarbonyl having 1-6 carbon atoms in the alkoxyl moiety; acyloxy comprising 2-10 carbon atoms; carbamoyl and mono- and dialkylcarbamoyl wherein the alkyl groups have 1-4 carbon atoms; and the non-critical counter anion, A, is representatively selected to provide pharmaceutically acceptable salts such as halides (chloro, bromo and the like), sulfate, phosphate, citrate acetate, benzoate and the like. Relative to the definition of A, it should be noted that embodiments of the present invention wherein X=oxygen and R.sup.4 is hydrogen are best considered to be zwitterions of the following structural representation (I): ##STR5## PA1 (i) R.sup.4 .dbd.CR.sup.a R.sup.b R.sup.c wherein at least one of R.sup.a, R.sup.b and R.sup.c is an electron-donor, e.g., p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, CH.sub.2 SCH.sub.3, tetrahydrofur-2-yl, tetrahydropyran-2-yl or fur-2-yl. The remaining R.sup.a, R.sup.b and R.sup.c groups may be hydrogen or organic substituting groups. Suitable ester groups of this type include p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl. PA1 (ii)R.sup.4 .dbd.CR.sup.a R.sup.b R.sup.c wherein at least one of R.sup.a, R.sup.b and R.sup.c is an electron-attracting group, e.g., benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulphonylmethyl, 2-dimethylsulphoniummethyl, o-nitrophenyl or cyano. Suitable esters of this type include benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl. PA1 (iii)R.sup.4 .dbd.CR.sup.a R.sup.b R.sup.c wherein at least two of R.sup.a, R.sup.b and R.sup.c are hydrocarbon such as alkyl, e.g., methyl or ethyl, or aryl, e.g., phenyl and the remaining R.sup.a, R.sup.b and R.sup.c group, if there is one, is hydrogen. Suitable esters of this type include t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl. PA1 (iv)R.sup.4 .dbd.R.sup.d, wherein R.sup.d is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl or tetrahydropyran-2-yl. PA1 R.sup.4'.sub.3 SiX'; R.sup.4'.sub.2 SiX'.sub.2 ; R.sup.4'.sub.3 Si.NR.sup.4'.sub.2 ; R.sup.4'.sub.3 Si.NH.COR.sup.4' ; PA1 R.sup.4'.sub.3 Si.NH.CO.NH.SiR.sup.4'.sub.3 ; R.sup.4' NH.CO.NH.SiR.sup.4'.sub.3 ; or R.sup.4' C(OSiR.sup.4'.sub.3); PA1 HN(SiR.sup.4'.sub.3).sub.2 wherein X' is a halogen such as chloro or bromo and the various groups R.sup.4', which can be the same or different, represent hydrogen atoms or alkyl, e.g., methyl, ethyl, n-propyl, iso-propyl; aryl, e.g., PA1 phenyl; or aralkyl, e.g., benzyl groups. PA1 (1) Amidines (R.sup.6 =H, or R); PA1 (2) Guanidines (R.sup.6 =NR.sup.1 R.sup.2); and PA1 (3) Substituted Pseudoureas (R.sup.6 =OR, or SR); wherein all symbolism is as defined above. PA1 (1) The reaction of a nitrile, RCN, with a lower alkanol in the presence of HCl according to the well-known Pinner synthesis. PA1 (2) The reaction of a nitrile, RCN, with a lower alkanol in the presence of a base. Typically, the reaction is conducted at 0.degree.-40.degree. C. in the presence of an excess of the alcohol with a catalytic amount of an alkali metal alkoxide for from 15 minutes to 4 hours. PA1 (3) The reaction of an amide, ##STR45## with an alkylchloroformate, such as methylchloroformate at 25.degree. C.-45.degree. C. for 1-4 hours. PA1 (4) The reaction of an N-substituted amide, ##STR46## with an equivalent of an alkylating agent such as triethyloxonium fluoroborate in an inert solvent such as ether, chloroform or the like at 0.degree.-23.degree. C. for from 10 minutes to 2 hours. PA1 (5) The conversion of a readily available imido ester, ##STR47## (R' may be hydrogen), to a desired imido ester, ##STR48## by reaction of the first-mentioned with an alkylamine, R'NH.sub.2, in a mixture of water and an immiscible solvent such as ether or chloroform at 0.degree.-23.degree. C. for from 5 minutes to 1 hour.
Thienamycin, the parent compounds is disclosed and claimed in U.S. Pat. No. 3,950,357 issued Apr. 13, 1976. This patent is incorporated herein by reference since thienamycin may be employed as a starting material in the preparation of the compounds of the present invention. Thienamycin is known to have the following structure: ##STR6## Starting material II (including all isomers and mixtures of isomers thereof) is also available by the total synthesis which is described and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 792,071, filed Apr. 28, 1977, of Christensen, Johnston, Schmitt now abandoned in favor of U.S. patent application Ser. No. 17,680, filed Mar. 5, 1979, now U.S. Pat. No. 4,234,596, issued Nov. 18, 1980. This application is incorporated herein by reference since it makes available all isomers, pure and as mixture, of II which are suitable starting materials for the preparation of the compounds of the present invention. Another convenient starting material for preparation of the compounds of the present invention is N-alkylated thienamycin and its O- and carboxyl derivatives (III): ##STR7## wherein R.sup.3, X, R.sup.4 and R.sup.5 are as defined above. The N-alkylated thienamycins (III) are disclosed and claimed in co-pending U.S. patent application Ser. No. 733,611 filed Oct. 18, 1976 now abandoned in favor of U.S. patent application Ser. No. 861,235, filed Dec. 16, 1977, now U.S. Pat. No. 4,235,920, issued Nov. 25, 1980. This application is incorporated herein by reference for its disclosure relative to the preparation of N-alkyl thienamycins defined by III, above.
Reference is made to commonly assigned, co-pending U.S. patent application Ser. No. 733,654 filed Oct. 18, 1976 now abandoned in favor of U.S. patent application Ser. No. 852,425, filed Nov. 17, 1977, now U.S. Pat. No. 4,194,047, issued Mar. 18, 1980 which discloses and claims N-iminomethyl derivatives of thienamycin (IV): ##STR8## wherein R.sup.3, X, R.sup.4, R.sup.1 and R.sup.2 are as defined above. This application is incorporated herein by reference as it discloses the preparation of IV (above) from thienamycin II (above). It should be noted that the preparation of species IV from II ((II.fwdarw.IV) is exactly analogous to the preparation of the compounds of the present invention I from III (III.fwdarw.I).
Finally, reference is made to commonly assigned, concurrently filed U.S. patent application Ser. No. 793,974, (filed May 5, 1977, now U.S. Pat. No. 4,235,917, issued Nov. 25, 1980) which discloses N-alkyl, N-acyl derivatives of thienamycin: ##STR9## wherein R.sup.3, X, R.sup.4 and R.sup.5 are as defined above and R' is acyl. This application is incorporated herein by reference, since the species IVa is required in the preparation of embodiments of I when R.sup.6 is OR or SR.
There is a continuing need for new antibiotics. For unfortunately there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly the search for new antibiotics continues.
Unexpectedly, it has been found that the compounds of the present invention are broad spectrum antibiotics, which are useful in animal and human therapy and in inanimate systems.
Thus, it is an object of the present invention to provide a novel class of antibiotics which possess the basic nuclear structure of the antibiotic thienamycin but which are characterized as N-alkyl-N-iminomethyl derivatives thereof. These antibiotic are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes and B. subtilis and gram negative bacteria such as E. coli, Proteus morganii, Serratia, Pseudomenas and Kiebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.